Genomic autopsy to identify underlying causes of pregnancy loss and perinatal death
Authors: Alicia B. Byrne, Peer Arts, Thuong T. Ha, Karin S. Kassahn, Lynn S. Pais, Anne O’Donnell-Luria, François Aguet, Harindra M. Arachchi, Christina A. Austin-Tse, Larry Babb, Samantha M. Baxter, Harrison Brand, Jaime Chang, Katherine R. Chao, Ryan L. Collins, Beryl Cummings, Kayla Delano, Stephanie P. DiTroia, Eleina England, Emily Evangelista, Selin Everett, Laurent C. Francioli, Jack Fu, Vijay S. Ganesh, Kiran V. Garimella, Laura D. Gauthier, Julia K. Goodrich, Sanna Gudmundsson, Stacey J. Hall, Yongqing Huang, Steve Jahl, Kristen M. Laricchia, Kathryn E. Larkin, Monkol Lek, Gabrielle Lemire, Rachel B. Lipson, Alysia Kern Lovgren, Daniel G. MacArthur, Brian E. Mangilog, Stacy Mano, Jamie L. Marshall, Thomas E. Mullen, Kevin K. Nguyen, Emily O’Heir, Melanie C. O’Leary, Ikeoluwa A. Osei-Owusu, Jorge Perez de Acha Chavez, Emma Pierce-Hoffman, Heidi L. Rehm, Jillian Serrano, Moriel Singer-Berk, Hana Snow, Matthew Solomonson, Rachel G. Son, Abigail Sveden, Michael Talkowski, Grace Tiao, Miriam S. Udler, Zaheer Valivullah, Elise Valkanas, Grace E. VanNoy, Qingbo S. Wang, Nicholas A. Watts, Ben Weisburd, Clara E. Williamson, Michael W. Wilson, Lauren Witzgall, Monica H. Wojcik, Isaac Wong, Jordan C. Wood, Shifa Zhang, Milena Babic, Mahalia S. B. Frank, Jinghua Feng, Paul Wang, David M. Lawrence, Leila Eshraghi, Luis Arriola, John Toubia, Hung Nguyen, Disna Abeysuriya, Lesley C. Ades, David J. Amor, Susan Arbuckle, Madhura Bakshi, Bligh Berry, Tiffany Boughtwood, Adam Bournazos, Alessandra Bray, Fiona Chan, Yuen Chan, Clara Chung, Jonathan Clark, Jackie Collett, Alison Colley, Felicity Collins, Sandra Cooper, Mark A. Corbett, Jane E. Dahlstrom, Peter Dargaville, Janene Davies, Tenielle Davis, Jarrad Dearman, Jayanthi Dissanayake, Julia Dobbins, Helen Doyle, Andrew Dubowsky, Matt Edwards, Lisa J. Ewans, Mitali Fadia, Andrew Fennell, Keri Finlay, Andrew French, Kathryn Friend, Alison E. Gardner, Jozef Gecz, Nicole Graf, Eric A. Haan, Georgina Hollingsworth, Ari E. Horton, Denise Howting, Matthew F. Hunter, Gareth Jevon, Benjamin Kamien, Debra Kennedy, T. Yee Khong, Michael Krivanek, Thessa Kroes, Emma I. Krzesinski, Edward Kwan, Stephanie Lau, Shannon LeBlanc, Jan Liebelt, Suzanna Lindsey-Temple, Jill Lipsett, Christine K. C. Loo, Julia Low, Amali Mallawaarachchi, Nick Manton, Admire Matsika, Tessa Mattiske, Julie McGaughran, Lesley McGregor, Namita Mittal, Ali Moghimi, Lynette Moore, Hatice Mutlu Albayrak, Jessica Ng, Jillian Nicholl, Nicholas Pachter, John Papadimitriou, Renae Parker, Sarah Parsons, Chirag Patel, Rhonda Pawlowski, Luis A. Perez-Jurado, Jason R. Pinner, Katerina Politis, Cathryn Poulton, Theresa Power, Michael Quinn, Sulekha Rajagopalan, Matthew Regan, Jonathan Rodgers, Steuart Rorke, Rani Sachdev, Suzanne Sallevelt, Sarah A. Sandaradura, Maryam Shamassi, Roshan Shamon, Isabella Sherburn, Jennie Slee, Annalisa Solinas, Ella Sugo, Elizabeth Thompson, Sagarika Tripathy, Anand Vasudevan, Melisa Vazquez, Kunal Verma, Mthulisi Viki, Mathew Wallis, Dani L. Webber, Martin Weber, Karen Whale, Meredith Wilson, Lisa Worgan, Sui Yu, George McGillivray, Jason Pinner, Fiona McKenzie, Rebecca Morrow, Jill Lipsett, Nick Manton, T. Yee Khong, Lynette Moore, Jan E. Liebelt, Andreas W. Schreiber, Sarah L. King-Smith, Tristan S. E. Hardy, Matilda R. Jackson, Christopher P. Barnett, Hamish S. Scott
Journal: Nature Medicine (2023)

Abstract Pregnancy loss and perinatal death are devastating events for families. We assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who had experienced fetal or newborn death, providing a definitive or candidate genetic diagnosis in 105 families. Our cohort provides evidence of severe atypical in utero presentations of known genetic disorders and identifies novel phenotypes and disease genes. Inheritance of 42% of definitive diagnoses were either autosomal recessive (30.8%), X-linked recessive (3.8%) or autosomal dominant (excluding de novos, 7.7%), with risk of recurrence in future pregnancies. We report that at least ten families (5%) used their diagnosis for preimplantation (5) or prenatal diagnosis (5) of 12 pregnancies. We emphasize the clinical importance of genomic investigations of pregnancy loss and perinatal death, with short turnaround times for diagnostic reporting and followed by systematic research follow-up investigations. This approach has the potential to enable accurate counseling for future pregnancies.